ABSTRACT Thyroid cancer is the most rapidly increasing cancer in the United States and it is now the fifth most prevalent cancer in women. Although most thyroid cancers are curable, a subset (~2-5% in the United States and up to 15% worldwide) is invariably fatal. Because these aggressive thyroid cancers lack effective therapies, they account for 40-50% of total thyroid cancer deaths. Genetic, immunohistochemical, epigenetic and animal model studies show that activation of the PI3K/AKT pathway is a pivotal event as thyroid tumors progress from low grade to aggressive subtypes such as anaplastic thyroid cancer (ATC). We have recently provided compelling in vitro and in vivo evidence that the loss or inhibition of the PI3K effector serum and glucocorticoid- regulated kinase 1 (SGK1) profoundly impacts thyroid cancer cell proliferation and survival, despite intact PI3K and AKT activity. This indicates that SGK1 is an integral and essential part of the PI3K transforming machinery and thus represents a novel therapeutic target for ATC. To find leads for this historically difficult target, we used our innovative Leap-to-Lead? platform, a computational and fragment-based lead discovery approach, to identify multiple novel series of SGK1 inhibitors. With low molecular weight, desirable physicochemical properties and chemical novelty, these series provide excellent medicinal chemistry starting points. Overcoming a specific limitation in previous SGK1 inhibitors, we achieved potent cellular activity and biomarker (pNDRG1) modulation after generating analogs in one series. Further, we developed improved synthetic methods that enable facile medicinal chemistry optimization in this series and supported the intellectual property position of this series with a provisional patent filing. In this Phase I SBIR, we will provide proof-of- concept efficacy data in an in vivo model of ATC after optimizing a series of SGK1 inhibitors. An SGK1 inhibitor series will progress through lead optimization using our Leap-to-Lead? platform, a validated assay cascade (enzyme inhibition, cellular proliferation, biomarker, pharmacokinetic) and our medicinal chemistry expertise. Optimized leads will be tested in a xenograft model of ATC at Albert Einstein College of Medicine in the laboratory of our collaborator, Dr. Antonio Di Cristofano, a recognized leader in thyroid cancer research Successful completion of the Phase I SBIR milestones will justify in vivo optimization and preclinical development of the lead series in Phase II SBIR studies with the goals of optimizing in vivo efficacy in animal models of human ATC and poorly differentiated thyroid cancer (PDTC), a thyroid cancer variant that shares many features with ATC. Finally, safety, pharmacology and toxicology profiles will be used in Phase II to select a candidate for IND-enabling studies.